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© 2000 American Society for Clinical Oncology
Concurrent Chemotherapy and Pelvic Radiation Therapy Compared With Pelvic Radiation Therapy Alone as Adjuvant Therapy After Radical Surgery in High-Risk Early-Stage Cancer of the CervixByFrom the Puget Sound Oncology Consortium; and Southwest Oncology Group Statistical CenterSeattle, WA; Bowman Gray School of Medicine, Winston-Salem, NC; Walter Reed Army Medical Center, Washington, DC; University of California at Irvine, Irvine; University of California at Los Angeles, Los Angeles, CA; McGill University, Montreal, Quebec, Canada; Mallinckrodt Institute of Radiology, St Louis, MO; Clear Lake Regional Medical Center, Webster, TX; University of Arizona Cancer Center, Tucson, AZ. Address reprint requests to Southwest Oncology Group (SWOG 8797), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.
PURPOSE: To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma. PATIENTS AND METHODS: Patients with clinical stage IA2, IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m2 and a 96-hour infusion of fluorouracil 1,000 mg/m2/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT. RESULTS: Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P = .003) and 1.96 (P = .007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group. CONCLUSION: The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.
BOTH RADICAL HYSTERECTOMY with pelvic lymphadenectomy and radical radiation therapy (RT) are used as primary therapy for early-stage carcinoma of the cervix. Comparison studies suggest that the overall 5-year survival rates are similar and, for patients with stage IB lesions, are in the 80% to 90% range.1-3 According to a patterns-of-care study performed by the American College of Surgeons, surgery is increasingly being used in the United States as the primary mode of treatment.4,5 Patients with stage IA2 and IIA are treated in a similar fashion to patients with stage IB lesions. Recurrences are much more frequent in patients with lymph node involvement and involvement of the parametrium or surgical margins and in patients with large or deeply invasive lesions.1,2,6-14 When one or more of these factors is found, the 5-year survival drops to the 50% to 70% range. After radical hysterectomy, adjuvant RT has commonly been used for patients at high risk for recurrence. Retrospective comparisons of patients with positive pelvic lymph nodes treated with postoperative RT have generally shown a decrease in the local recurrence rate but no improvement in long-term survival.15,16 Several small phase II studies have suggested a potential benefit for adjuvant chemotherapy (CT) in high-risk patients, with the combination of cisplatin and fluorouracil (5-FU) demonstrating activity in patients with advanced or metastatic cervical cancer.17-19 Both cisplatin and 5-FU are radiation sensitizers and their concurrent use seems to be synergistic.20 The concurrent use of cisplatin (with or without 5-FU) and pelvic irradiation in patients with advanced disease seemed to improve local control and overall survival in phase II trials, as well as four recently reported phase III trials.21-25 The current study was designed to see if the addition of CT to standard pelvic RT could improve the progression-free survival and overall survival in patients at high risk for relapse after primary radical hysterectomy.
Eligibility Criteria Patients in this trial had undergone a type 3 radical hysterectomy with pelvic lymphadenectomy for a clinical stage IA2, IB, or IIA carcinoma of the cervix.26 Patients were eligible if they had a squamous carcinoma, adenocarcinoma, or an adenosquamous carcinoma and had histologically confirmed positive pelvic lymph nodes, positive parametrial involvement, or a positive surgical margin. Registration was required within 6 weeks of surgery, with RT to begin within 5 working days of registration. Patients randomized to the CT arm began CT on the same day that they began the RT. Patients were required to have a Southwest Oncology Group (SWOG) performance status of 0 to 2, a WBC count  3,000/µL, platelets 100,000/µL, and normal creatinine and bilirubin. All institutions participating in the protocol obtained the approval of their human investigation committee in accordance with local, state, and federal regulations, and all patients were entered onto the study after obtaining proper informed consent.
Treatment Plan For patients randomized to CT, treatment was begun on day 1 of their RT. One cycle of CT consisted of cisplatin 70 mg/m2 by 2-hour intravenous infusion given on day 1 and 5-FU at a dose of 1,000 mg/m2 per day for 4 days given as a 96-hour continuous infusion on days 1 to 4. The second cycle of CT began on day 22. The third and fourth cycles of CT were scheduled after completion of RT, to begin on days 43 and 64. Toxicity was defined by standard SWOG criteria.27
Treatment Modifications
During those weeks in which the patient did not receive CT, RT was continued as long as the WBC count was This intergroup study was open to patients from SWOG, the Gynecologic Oncology Group (GOG), and the Radiation Therapy Oncology Group (RTOG). Pertinent histopathologic sections from the biopsies and radical hysterectomies were submitted to the responsible study member (R.J.S.) of the Pathology Committee of GOG for review. The final histopathologic diagnostic categories were squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma. Lesion size was recorded as the greatest tumor diameter on histologic section. The diagnoses were based solely on hematoxylin and eosin–stained material.
Statistical Analysis Interim analyses were planned when approximately one quarter, one half, and three quarters of the anticipated deaths had occurred. Under standard SWOG guidelines, the decision for early termination or reporting of the study would be made by the SWOG Data and Safety Monitoring Committee, if warranted.28 The statistical guideline for initiating such considerations is if either the null hypothesis of no CT benefit or the alternative hypothesis of a 1.5 RT alone versus RT + CT hazard ratio is rejected at a 0.005 significance level for progression-free and/or overall survival. The actual decision would take into account other factors such as toxicities, complications, and data from other sources.
Between 1991 and 1996, 268 patients were entered onto this trial (19 patients from SWOG, 226 from GOG, and 23 from RTOG). Twenty-five patients were ineligible, leaving 243 assessable patients (127 patients in the CT + RT arm and 116 in the RT alone arm). After patient accrual was completed and the second interim analysis was performed for the study, results of several randomized trials in cervical cancer (GOG 85, 120, and 123) became available. The Data and Safety Monitoring Committee called for a special interim analysis and decided in April 1998 to release the results of the current study. The statistical boundaries for rejecting the null hypothesis of no CT benefits were crossed when the decision was made to early release the study results. Among the 25 ineligible patients, two patients were ineligible based on surgical review, four patients were ineligible on pathology review, and 19 patients had insufficient information or lack of submission of pathology material. In the CT + RT group, one patient was not treated because of a surgical complication, five patients refused CT, and four patients refused both the CT and RT. In the RT only arm, three patients refused RT and a fourth patient was never treated because of physician discretion. The nine patients (five CT + RT patients and four RT only patients) receiving no protocol treatment were not included in toxicity analysis. All 243 patients are included in survival analysis according to the intent-to-treat principle. The patient characteristics in the two arms are depicted in Table 1 and include age, race, clinical stage, primary lesion size, presence of positive pelvic lymph nodes, positive high common iliac lymph nodes, positive margins, parametrial involvement, and cell type. There are no statistically significant differences in any of the patient characteristics between the two arms.
Table 2 summarizes the completeness of the RT in the two treatment arms. Eighty-nine percent of the patients (113 of 127) randomized to CT + RT and 94% (109 of 116) randomized to RT alone received more than 45 Gy. These rates are not statistically different (Fisher’s exact test, P = .12). The details of time to RT completion for those who received more than 45 Gy are displayed in Table 3. Of those receiving more than 45 Gy, the median time to RT completion was 43 days (range, 35 to 79 days) for the CT + RT arm and 41 days (range, 38 to 65 days) for the RT only arm. This difference is statistically significant (Wilcoxon rank sum, P = .01).
Table 4 is a summary of the number of cycles of CT for patients randomized to CT + RT. Overall, 71% of patients received at least three cycles of CT. Of 27 patients who received only one or two cycles of CT, six patients were taken off of CT because of toxicity and one because of disease progression. The other 20 patients refused further therapy.
Survival Analysis At the time of this report, the median follow-up time is 42 months. Figure 1 is a Kaplan-Meier depiction of progression-free survival by treatment arm. Patients receiving CT + RT had a statistically significant improvement in progression-free survival. The estimated 4-year progression-free survival for patients receiving CT + RT was 80%, versus 63% for patients receiving RT alone. Figure 2 shows overall survival by treatment group. The estimated 4-year survivals were 81% for CT + RT and 71% for RT only. When adjusted for stratification factors (clinical stage, nodal involvement, and cooperative group), Cox model analysis projected an RT only versus RT + CT hazard ratio of 2.01 (P = .003) for progression-free survival and 1.96 (P = .007) for overall survival. The results were unchanged when age, race, parametrial involvement, positive surgical margins, and cell type were added to the Cox models. Of the variables included in the multivariate analyses, lesion size was the only statistically significant prognostic factor for progression-free survival (P = .05) and overall survival (P = .03).
Both pelvic and extrapelvic recurrences were less frequent in those patients receiving CT (Table 5). There is no statistically significant differences in the pattern of recurrence between the two treatment arms (  2 test, P = .20).
Fig 3 is a comparison of the Kaplan-Meier progression-free survival curves in patients randomized to RT alone by cell type. Patients with adenocarcinoma or adenosquamous carcinoma have a worse prognosis. As shown in Fig 4, this difference in prognosis for nonsquamous tumors disappears in patients who receive CT. When a treatment versus cell type (adenocarcinoma or adenosquamous carcinoma v squamous carcinoma) interaction was introduced to the Cox model, this difference in response to the addition of CT by cell type did not reach statistical significance (P = .12 for progression-free survival and P = .19 for overall survival).
Analyses were performed to explore potential associations between the number of courses of therapy received and survival. To avoid the bias introduced by short-term survivors’ inherent inability to receive higher numbers of treatment courses, survival was measured from 91 days after study registration, which was chosen because it was the median time to CT completion for those who received the entire four courses of therapy.29 Patients who died or for whom the disease recurred before 91 days were excluded from the relevant analyses. The resulting numbers of eligible patients were 124 for progression-free survival (three exclusions) and 125 for overall survival (two exclusions). Higher numbers of CT courses were favorably associated with both progression-free survival and overall survival (Cox model, P = .03 for both progression-free and overall survival) (Fig 5).
Toxicity Among the 122 patients assessable for toxicity in the CT + RT arm, there were 27 episodes of grade 4 toxicity in 21 patients (Table 6), most of which were hematologic. Among 112 patients randomized to RT alone and assessable for toxicity, four patients had grade 4 toxicity.
There was one late death in the series that may have been treatment-related. The patient was randomized to receive CT + RT but refused the CT and was treated with RT alone. Seventeen months after RT, she developed bilateral ureteral obstructions with fibrosis and renal failure, which was managed with chronic ureteral stents. She had a history of prior coronary artery disease and had a sudden unexplained death 39 months after completing RT.
Both radical RT and radical surgery have been considered appropriate for patients with stage IA2, IB, and IIA carcinoma of the cervix.1,2 A choice between these two modalities is frequently influenced by the availability of specialists, the age of the patient, and perceived toxicities. Since the establishment of subspecialty training in gynecologic oncology, radical surgery has been increasingly used in the United States as first-line therapy.4,5 It has long been recognized that survival after radical hysterectomy was impacted by lymph node status.1,2,8,10 Other high-risk factors have included margin status and parametrial involvement.6,11,14 More recent analyses of large series of radical hysterectomies have shown that depth of cervical stromal invasion, clinical lesion size, and patient age are also independent prognostic factors.2,9,10,13 The presence of tumor in lymph-vascular channels has been an independent factor in some analyses,8-10 whereas other analyses have not found this to be an independent risk factor.13 This trial was planned before the most recent clinical pathologic studies and does not include all patients who would currently be considered high risk. Postoperative pelvic RT has frequently been used for patients with positive pelvic lymph nodes. Although a few series have reported a survival benefit associated with postoperative irradiation, the preponderance of studies have only shown a decrease in the local failure rate and no improvement in survival.15,16 A recently completed study (GOG 92) compared RT after surgery with surgery alone in an intermediate-risk group.30 There was a reduction in the recurrence rate from 28% to 15% with the addition of RT. Because GOG 92 excluded patients with positive lymph nodes, it cannot be directly compared with the current study, but it does suggest that RT has a role in adjuvant therapy.
For high-risk postsurgical patients, several retrospective studies have suggested a benefit to cisplatin-based CT either given alone or before RT.31-36 In a small randomized trial, Curtin et al37 compared CT with CT + RT and showed the same relapse rate in a high-risk patient group. In another small randomized trial for node position patients, Tattersall et al38 compared RT with CT followed by RT and found no difference in disease-free or overall survival. Concomitant CT with RT has been shown to improve survival and reduce relapses in select groups of cervical cancer patients when compared with RT alone. In a randomized three-arm study performed by the GOG comparing the efficacy of hydroxyurea versus 5-FU infusion, hydroxyurea, and bolus cisplatin versus weekly bolus cisplatin as concomitant chemoradiation in advanced cervical cancer (stages IIB, III, and IVA), both platinum regimens were superior to hydroxyurea alone in reducing the risk of progression and death.22 For bulky stage IB cervical cancer, the GOG found improvement in the recurrence-free interval and survival for patients treated with weekly cisplatin during irradiation compared with RT alone. In this trial, both groups completed treatment with adjuvant hysterectomy.23 The RTOG has compared extended-field RT with pelvic RT + CT (concurrent cisplatin and 5-FU) for patients with stages IIB to IVA or bulky stages IB or IIA disease and found a significant survival advantage in the CT + RT group.24 In patients with stage IIB to IVA disease who were surgically staged and had negative paraaortic lymph nodes, a GOG/SWOG intergroup study compared pelvic RT plus hydroxyurea with pelvic RT plus concurrent cisplatin and 5-FU. There was an improvement in relapse-free and overall survival in the cisplatin plus 5-FU group.25 These large, randomized, prospective studies, when combined with the data from the present report, reveal a remarkably consistent advantage for chemoradiation over RT alone in patients with cervical cancer, including a wide range of stages, cell types, and other prognostic factors. Despite the patients refusing all CT and the substantial number of patients who did not complete all four cycles of CT, we saw a profound decrease in recurrence and an improvement in progression-free and overall survival with the addition of CT to pelvic RT. Despite a slightly longer total treatment time, the percentage of patients receiving It is not possible to determine from our analysis whether the effect of the CT was as a radiation sensitizer or as systemic CT with elimination of micrometastasis or both. The favorable survival seen in patients receiving the third and fourth cycles of CT after completion of RT would suggest that the CT was having an effect independent of the RT. However, such a conclusion can only be established from future randomized studies and not from the current data because of the possibility that patients with a poorer tolerance of CT have an inherently inferior prognosis independent of the total number of cycles. Regardless of the mechanism of action, we conclude that the addition of CT to RT significantly improves progression-free and overall survival for high-risk early-stage patients who undergo a radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix. It has been suggested that adenocarcinomas and adenosquamous carcinomas have a more ominous prognosis than squamous carcinomas, particularly if there is extracervical extension of the tumor.39 In this trial, adenocarcinomas and adenosquamous carcinomas had a poorer prognosis in patients with at least one other poor prognostic factor. Importantly, the addition of chemotherapy seems to improve disease-free survival in this subgroup of poor-prognosis patients.
Supported in part by National Cancer Institute Department of Health and Human Services Public Health Service Cooperative Agreement grant nos. CA38926, CA32102, CA35090, CA20319, CA45560, CA22433, CA13612, CA45377, CA35261, CA35178, CA25192, CA21661, CA37422, CA32115, CA27469, and CA37517.
1. Morley GW, Seski JC: Radical pelvic surgery versus radiation therapy for stage 1 carcinoma of the cervix (exclusive of microinvasion). Am J Obstet Gynecol 126:785-794, 1976[Medline] 2. Hopkins MP, Morley GW: Radical hysterectomy versus radiation therapy for stage IB squamous cell carcinoma of the cervix. Cancer 68:272-277, 1991[Medline] 3. Landoni F, Maneo A, Colombo A, et al: Randomised study of radical surgery versus radiotherapy for stages IB-IIA cervical cancer. Lancet 350:535-540, 1997[Medline] 4. Shingleton HM, Jones WB, Russell A, et al: Hysterectomy in invasive cervical cancer: A national patterns of care study of the American College of Surgeons. J Am Coll Surg 183:393-400, 1996[Medline] 5. Russell AH, Shingleton HM, Jones WB, et al: Trends in the use of radiation and chemotherapy in the initial management of patients with carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 40:605-613, 1998[Medline] 6. Inoue T, Okumura M: Prognostic significance of parametrial extension in patients with cervical carcinoma stages IB, IIA and IIB: A study of 628 cases treated by radical hysterectomy and lymphadenectomy with and without postoperative radiation. Cancer 54:1714-1719, 1984[Medline] 7. Alvarez RD, Soong SJ, Kinney WK, et al: Identification of prognostic factors and risk groups in patients found to have nodal metastasis at time of radical hysterectomy for early-stage squamous carcinoma of the cervix. Gynecol Oncol 35:130-135, 1989[Medline] 8. Fuller AF Jr, Elliott N, Kosloff C, et al: Determinants of increased risk for recurrence in patients undergoing radical hysterectomy for stage IA and IIB carcinoma of the cervix. Gynecol Oncol 33:34-39, 1989[Medline] 9. Delgado G, Bundy B, Zaino R, et al: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 38:352-357, 1990[Medline] 10. Sevin BU, Lu Y, Bloch BA, et al: Surgically defined prognostic parameters in patients with early cervical carcinoma: A multivariate survival tree analysis. Cancer 78:1438-1446, 1996[Medline] 11. Zreik TG, Chambers JT, Chambers SK: Parametrial involvement, regardless of nodal status: A poor prognostic factor for cervical cancer. Obstet Gynecol 87:741-746, 1996[Abstract] 12. Lin HH, Cheng WF, Chan KW, et al: Risk factors for recurrence in patients with stage IB, IIA and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation. Obstet Gynecol 88:274-279, 1996[Abstract] 13. Kamura T, Tsukamoto N, Tsuruchi N, et al: Multivariate analysis of the histopathologic prognostic factors of cervical cancer in patients undergoing radical hysterectomy. Cancer 69:181-186, 1992[Medline] 14. Estape RE, Angioli R, Madrigal M, et al: Close vaginal margins as a prognostic factor after radical hysterectomy. Gynecol Oncol 68:229-232, 1998[Medline] 15. Morrow CP, Shingleton HM, Averette HE, et al: Is pelvic radiation beneficial in the postoperative management of stage IB squamous cell carcinoma of the cervix with pelvic node metastasis treated by radical hysterectomy and pelvic lymphadenectomy? A report from the Presidential Panel at the 1979 Annual Meeting of the Society of Gynecologic Oncologists. Gynecol Oncol 10:105-110, 1980[Medline] 16. Kinney WK, Alvarez RD, Reid GC, et al: Value of adjuvant whole-pelvis irradiation after Wertheim hysterectomy for early-stage squamous carcinoma of the cervix with pelvic nodal metastasis: A matched-control study. Gynecol Oncol 34:258-262, 1989[Medline] 17. Rotmensch J, Senekjian EK, Javaheri G, et al: Evaluation of bolus cis-platinum and continuous 5-fluorouracil infusion for metastatic and recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 29:76-81, 1988[Medline] 18. Bonomi P, Blessing J, Ball H, et al: A phase II evaluation of cisplatin and 5-fluorouracil in patients with advanced squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 34:357-359, 1989[Medline] 19. Weiss GR, Green S, Hannigan EV, et al: A phase II trial of cisplatin and 5-fluorouracil with allopurinol for recurrent or metastatic carcinoma of the uterine cervix: A Southwest Oncology Group trial. Gynecol Oncol 37:354-358, 1990[Medline] 20. Vokes EE, Weichselbaum RR: Concomitant chemoradiotherapy: Rationale and clinical experience in patients with solid tumors. J Clin Oncol 8:911-934, 1990[Abstract] 21. Roberts WS, Kavanagh JJ, Greenberg H, et al: Concomitant radiation therapy and chemotherapy in the treatment of advanced squamous carcinoma of the lower female genital tract. Gynecol Oncol 34:183-186, 1989[Medline]
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Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340:1144-1153, 1999
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Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154-1161, 1999
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Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137-1143, 1999
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Whitney CW, Sause W, Bundy BN, et al: Randomized Comparison of fluorouracil plus cisplatin versus hydroxyurea on an adjuvant to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17:1339-1348, 1999
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Hopkins MP, Morley GW: A comparison of adenocarcinoma and squamous cell carcinoma of the cervix. Obstet Gynecol 77:912-917, 1991 Submitted November 3, 1999; accepted February 8, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
